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CHNG4
MCID: HYP795
MIFTS: 47

Hypothyroidism, Congenital, Nongoitrous, 4 (CHNG4)

Categories: Bone diseases, Endocrine diseases, Genetic diseases, Neuronal diseases, Rare diseases
Genes Variations Tissues Related diseases Publications Pathways Symptoms & Phenotypes Drugs
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Aliases & Classifications for Hypothyroidism, Congenital, Nongoitrous, 4

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MalaCards integrated aliases for Hypothyroidism, Congenital, Nongoitrous, 4:

Name: Hypothyroidism, Congenital, Nongoitrous, 4 56 71
Tsh Deficiency 56 52 54
Congenital Nongoitrous Hypothyroidism 4 12 15
Thyrotropin Deficiency, Isolated 56 52
Isolated Thyrotropin Deficiency 12 58
Isolated Tsh Deficiency 58 36
Pituitary Cretinism 56 52
Chng4 56 12
Isolated Thyroid-Stimulating Hormone Deficiency 58
Hypothyroidism, Congenital, Nongoitrous, Type 4 39
Thyroid-Stimulating Hormone, Deficiency of 52
Hypothyroidism, Congenital, Nongoitrous 4 56
Thyroid-Stimulating Hormone Deficiency 56
Secondary Hypothyroidism 71

Characteristics:

Orphanet epidemiological data:

58
isolated thyroid-stimulating hormone deficiency
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal;

OMIM:

56
Inheritance:
autosomal recessive


HPO:

31
hypothyroidism, congenital, nongoitrous, 4:
Inheritance autosomal recessive inheritance


Classifications:

MalaCards categories:
Global: Genetic diseases Rare diseases
Anatomical: Endocrine diseases Neuronal diseases Bone diseases
See all MalaCards categories (disease lists)
ICD10: 32 33
Orphanet: 58  
Rare endocrine diseases


External Ids:

Disease Ontology 12 DOID:0070123
OMIM 56 275100
OMIM Phenotypic Series 56 PS275200
KEGG 36 H01699
ICD10 32 E03.1
ICD10 via Orphanet 33 E03.1
Orphanet 58 ORPHA90674
MedGen 41 C0271789
UMLS 71 C0271789 C3665349
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Summaries for Hypothyroidism, Congenital, Nongoitrous, 4

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KEGG : 36 Isolated TSH deficiency is a rare autosomal recessive disease, that cause congenital hypothyroidism. Patients were found to have homozygous splice site mutation in the TSH beta subunit gene. They show symptoms of severe mental and growth retardation that can be prevented by early administration of exogenous thyroid hormone. Levothyroxine replacement therapy is the treatment of choice. Concomitant corticotropin deficiency should be excluded prior to starting therapy in order to avoid an adrenal crisis.

MalaCards based summary : Hypothyroidism, Congenital, Nongoitrous, 4, also known as tsh deficiency, is related to combined pituitary hormone deficiency and adenohypophysitis. An important gene associated with Hypothyroidism, Congenital, Nongoitrous, 4 is TSHB (Thyroid Stimulating Hormone Subunit Beta), and among its related pathways/superpathways are Thyroid hormone synthesis and Relaxin signaling pathway. The drugs Dopamine and Sympathomimetics have been mentioned in the context of this disorder. Affiliated tissues include thyroid, pituitary and brain, and related phenotypes are sleep disturbance and constipation

Disease Ontology : 12 A congenital hypothyroidism characterized by a permanent thyroid deficiency present at birth and resulting from deficiency in TSH synthesis that has material basis in homozygous mutation in the TSHB gene on chromosome 1p13.

More information from OMIM: 275100 PS275200
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Related Diseases for Hypothyroidism, Congenital, Nongoitrous, 4

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Diseases in the Hypothyroidism, Congenital, Nongoitrous, 2 family:

Hypothyroidism, Congenital, Nongoitrous, 5 Hypothyroidism, Congenital, Nongoitrous, 4
Hypothyroidism, Congenital, Nongoitrous, 1 Hypothyroidism, Congenital, Nongoitrous, 8
Hypothyroidism, Congenital, Nongoitrous, 9 Hypothyroidism, Congenital, Nongoitrous, 3
Hypothyroidism, Congenital, Nongoitrous, 6 Hypothyroidism, Congenital, Nongoitrous, 7

Diseases related to Hypothyroidism, Congenital, Nongoitrous, 4 via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 120)
# Related Disease Score Top Affiliating Genes
1 combined pituitary hormone deficiency 29.6 PROP1 POU1F1
2 adenohypophysitis 29.0 PRL POMC GH1
3 congenital hypothyroidism 28.7 TSHB PRL POU1F1 GH1
4 empty sella syndrome 28.5 PROP1 PRL POMC GH1
5 isolated growth hormone deficiency 28.4 PROP1 POU1F1 POMC GH1
6 adenoma 28.3 PRL POU1F1 POMC GH1
7 pituitary adenoma 27.9 TSHB PRL POU1F1 POMC GH1
8 hypothyroidism 27.4 TSHB PROP1 PRL POU1F1 POMC GH1
9 pituitary hormone deficiency, combined, 2 27.2 TSHB PROP1 PRL POU1F1 POMC GH1
10 pituitary gland disease 27.2 TSHB PROP1 PRL POU1F1 POMC GH1
11 thyroid-stimulating hormone level quantitative trait locus 1 11.3
12 central congenital hypothyroidism 11.2
13 fibrous dysplasia 10.1 PRL GH1
14 fibrous dysplasia/mccune-albright syndrome 10.1 PRL GH1
15 mccune-albright syndrome 10.1 PRL GH1
16 gigantism 10.1 PRL GH1
17 tetrahydrobiopterin deficiency 10.1 PRL GH1
18 pseudohypoparathyroidism, type ia 10.0 PRL GH1
19 pituitary adenoma 1, multiple types 10.0 PRL GH1
20 thyroiditis 10.0 TSHB PRL
21 hypothyroidism due to deficient transcription factors involved in pituitary development or function 10.0 PROP1 POU1F1
22 acanthosis nigricans 10.0 PRL GH1
23 combined pituitary hormone deficiencies, genetic forms 10.0 PROP1 POU1F1
24 goiter 10.0
25 dwarfism 10.0
26 suprasellar meningioma 9.9 TSHB POMC
27 borjeson-forssman-lehmann syndrome 9.9 PROP1 POU1F1
28 acth-dependent cushing syndrome 9.9 PRL POMC
29 tuberculum sellae meningioma 9.9 PRL POMC
30 sella turcica neoplasm 9.9 PRL POMC
31 prolactin producing pituitary tumor 9.9 PRL POMC
32 occipital horn syndrome 9.9
33 cutis laxa 9.9
34 adrenal adenoma 9.9
35 myotonic dystrophy 9.9
36 differentiated thyroid carcinoma 9.9
37 premature aging 9.9
38 thyroid carcinoma 9.9
39 pituitary infarct 9.9 PRL POMC
40 acidophil adenoma 9.9 PRL POMC
41 insulin-like growth factor i 9.9 PRL GH1
42 abducens nerve disease 9.9 PRL POMC
43 hormone producing pituitary cancer 9.9 PRL POMC
44 sheehan syndrome 9.9 PRL POMC
45 gangliocytoma 9.9 PRL POMC
46 benign essential hypertension 9.8 PRL POMC
47 nelson syndrome 9.8 PRL POMC
48 cranial nerve palsy 9.8 PRL POMC
49 acth-secreting pituitary adenoma 9.8 PRL POMC
50 lymphocytic hypophysitis 9.8 POMC GH1

Graphical network of the top 20 diseases related to Hypothyroidism, Congenital, Nongoitrous, 4:



Diseases related to Hypothyroidism, Congenital, Nongoitrous, 4
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Symptoms & Phenotypes for Hypothyroidism, Congenital, Nongoitrous, 4

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Human phenotypes related to Hypothyroidism, Congenital, Nongoitrous, 4:

58 31 (show all 22)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 sleep disturbance 58 31 hallmark (90%) Very frequent (99-80%) HP:0002360
2 constipation 58 31 hallmark (90%) Very frequent (99-80%) HP:0002019
3 hypothyroidism 58 31 hallmark (90%) Very frequent (99-80%) HP:0000821
4 muscular hypotonia 58 31 hallmark (90%) Very frequent (99-80%) HP:0001252
5 macroglossia 58 31 hallmark (90%) Very frequent (99-80%) HP:0000158
6 coarse facial features 58 31 hallmark (90%) Very frequent (99-80%) HP:0000280
7 umbilical hernia 58 31 hallmark (90%) Very frequent (99-80%) HP:0001537
8 feeding difficulties 58 31 hallmark (90%) Very frequent (99-80%) HP:0011968
9 fatigue 58 31 hallmark (90%) Very frequent (99-80%) HP:0012378
10 jaundice 58 31 hallmark (90%) Very frequent (99-80%) HP:0000952
11 large fontanelles 58 31 hallmark (90%) Very frequent (99-80%) HP:0000239
12 abdominal distention 58 31 hallmark (90%) Very frequent (99-80%) HP:0003270
13 depressed nasal bridge 31 HP:0005280
14 hoarse cry 31 HP:0001615
15 intellectual disability, severe 31 HP:0010864
16 abnormality of metabolism/homeostasis 31 HP:0001939
17 generalized hypotonia 31 HP:0001290
18 intellectual disability, progressive 31 HP:0006887
19 wide anterior fontanel 31 HP:0000260
20 omphalocele 31 HP:0001539
21 severe postnatal growth retardation 31 HP:0008850
22 congenital hypothyroidism 31 HP:0000851

Symptoms via clinical synopsis from OMIM:

56
Head And Neck Mouth:
macroglossia

Abdomen External Features:
umbilical hernia
omphalocele (rare)

Muscle Soft Tissue:
hypotonia

Neurologic Central Nervous System:
mental retardation, severe (if untreated)

Skeletal Skull:
large anterior fontanelle
open posterior fontanelle

Head And Neck Nose:
depressed nasal bridge

Voice:
hoarse cry

Growth Other:
growth retardation, severe (if untreated)

Endocrine Features:
hypothyroidism, nongoitrous

Laboratory Abnormalities:
low to normal tsh (values may vary depending on the measurement methods used)

Clinical features from OMIM:

275100
Sources

Drugs & Therapeutics for Hypothyroidism, Congenital, Nongoitrous, 4

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Drugs for Hypothyroidism, Congenital, Nongoitrous, 4 (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 6)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Dopamine Approved Phase 3 51-61-6, 62-31-7 681
2 Sympathomimetics Phase 3
3 Neurotransmitter Agents Phase 3
4 Dopamine Agents Phase 3
5 Autonomic Agents Phase 3
6 Protective Agents Phase 3

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 A Randomised, Controlled, Crossover Study: Treatment With Thyroxin Compared to Thyroxin + Triiodothyronin in Patients With Secondary Hypothyroidism Completed NCT00360074 Phase 4 Thyroxin, Triiodothyronine
2 Management of Hypotension In Preterm Infants: The HIP Trial Protocol for a Randomized Controlled Trial of Hypotension Management in the Extremely Low Gestational Age Newborn Terminated NCT01482559 Phase 3 Dopamine hydrochloride;Dextrose 5%

Search NIH Clinical Center for Hypothyroidism, Congenital, Nongoitrous, 4

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Genetic Tests for Hypothyroidism, Congenital, Nongoitrous, 4

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Anatomical Context for Hypothyroidism, Congenital, Nongoitrous, 4

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MalaCards organs/tissues related to Hypothyroidism, Congenital, Nongoitrous, 4:

40
Thyroid, Pituitary, Brain, Bone, Heart, Testes, T Cells
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Publications for Hypothyroidism, Congenital, Nongoitrous, 4

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Articles related to Hypothyroidism, Congenital, Nongoitrous, 4:

(show top 50) (show all 216)
# Title Authors PMID Year
1
New autosomal recessive mutation of the TSH-beta subunit gene causing central isolated hypothyroidism. 54 61 56 6
11549695 2001
2
Four new cases of congenital secondary hypothyroidism due to a splice site mutation in the thyrotropin-beta gene: phenotypic variability and founder effect. 61 56 6
15292359 2004
3
Congenital central hypothyroidism due to homozygous thyrotropin beta 313 Delta T mutation is caused by a Founder effect. 61 56 6
12364478 2002
4
Congenital secondary hypothyroidism caused by exon skipping due to a homozygous donor splice site mutation in the TSHbeta-subunit gene. 61 56 6
11788671 2002
5
Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin beta-subunit gene follows an autosomal recessive inheritance. 61 56 6
9589689 1998
6
Familial hypothyroidism caused by a nonsense mutation in the thyroid-stimulating hormone beta-subunit gene. 61 56 6
1971148 1990
7
Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta-subunit. 61 56 6
2792087 1989
8
Hyperplastic pituitary gland, high serum glycoprotein hormone alpha-subunit, and variable circulating thyrotropin (TSH) levels as hallmark of central hypothyroidism due to mutations of the TSH beta gene. 56 6
11297590 2001
9
A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene. 56 6
8636437 1996
10
Pituitary cretinism in two sisters. 61 56
7436542 1980
11
Elevated plasma TSH and hypothyroidism in children with hypothalamic hypopituitarism. 61 56
809459 1975
12
Isolated thyrotropin deficiency in a man with narcoleptic attacks. 56
6293273 1982
13
Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin. 56
109460 1979
14
The secretion of thyrotrophin with impaired biological activity in patients with hypothalamic-pituitary disease. 56
647990 1978
15
Glandular end organ deficiency associated with secretion of biologically inactive pituitary peptides. 56
4364811 1974
16
Enzymatic synthesis of thyrotropin releasing hormone (TRH) by hypothalamic "TRH synthetase". 56
4627366 1972
17
Familial isolated thyrotropin deficiency with cretinism. 56
4106196 1971
18
Hypothalamic hypothyroidism. 56
4998943 1971
19
Studies in pseudohypoparathyroidism. Two new cases with a probable selective deficiency of thyrotropin. 56
5780370 1969
20
Thyrotropin hormone deficiency with a peripheral neuropathy. 56
4301577 1968
21
Isolated lack of thyrotropin in man. 56
5926947 1966
22
W194XProp1 and S156insTProp1, both of which have intact DNA-binding domain, show a different DNA-binding activity to the Prop1-binding element in human Pit-1 gene. 54 61
20381582 2010
23
Hypopituitarism oddities: congenital causes. 54 61
18174732 2007
24
Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. 54 61
16735499 2006
25
A case of macroprolactinoma and elevated insulin-like growth factor-I in a young boy. 54 61
16421054 2005
26
Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. 54 61
15928241 2005
27
PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. 54 61
15472232 2004
28
DNA testing in patients with GH deficiency at the time of transition. 54 61
12914740 2003
29
Efficacy of radiotherapy in normalizing serum IGF-I, acid-labile subunit (ALS) and IGFBP-3 levels in acromegaly. 54 61
11531924 2001
30
Severe hypoglycemia and reduction of insulin requirement in a girl with insulin-dependent diabetes mellitus: first sign of a craniopharyngioma. 54 61
10703545 1999
31
Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg-->Cys at codon 120 (R120C). 54 61
9768691 1998
32
Genetic basis of congenital hypothyroidism: abnormalities in the TSHbeta gene, the PIT1 gene, and the NIS gene. 54 61
9806481 1998
33
Autosomal recessive deficiency of combined pituitary hormones (except ACTH) in a consanguineous Brazilian kindred. 54 61
9699131 1998
34
Rarity of PIT1 involvement in children from Russia with combined pituitary hormone deficiency. 54 61
9632165 1998
35
Pro239Ser: a novel recessive mutation of the Pit-1 gene in seven Middle Eastern children with growth hormone, prolactin, and thyrotropin deficiency. 54 61
9626142 1998
36
Description of a Brazilian patient bearing the R271W Pit-1 gene mutation. 54 61
9588494 1998
37
Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene. 54 61
9485179 1998
38
Autosomal recessive deficiency of combined pituitary hormones (except ACTH) in a consanguineous Brazilian kindred. 54 61
9438923 1997
39
GH and TSH deficiency. 54 61
9439906 1997
40
[Homeoproteins and pituitary adenoma]. 54 61
9207961 1997
41
[Molecular genetics of congenital isolated thyrotropin deficiency]. 54 61
8196185 1994
42
Congenital hypothyroidism: etiology and pathogenesis. 54 61
7879996 1994
43
[Mechanism of regulation of TSH--biosynthesis and secretion]. 54 61
8254929 1993
44
Genetics of growth hormone gene expression. 54 61
8300051 1993
45
[Acquired corticotropin insufficiency in adults. 2 new cases]. 54 61
8191076 1993
46
Rapid detection of a point mutation in thyroid-stimulating hormone beta-subunit gene causing congenital isolated thyroid-stimulating hormone deficiency. 54 61
1811097 1991
47
A case of severe pituitary dwarfism associated with prolactin and thyroid stimulating hormone deficiencies. 54 61
2085115 1990
48
Deoxyribonucleic acid analyses of five families with familial inherited thyroid stimulating hormone deficiency. 54 61
2401711 1990
49
Routine free thyroxine reference intervals are suboptimal for monitoring children on thyroxine replacement therapy and target intervals need to be assay-specific. 61
31836869 2019
50
Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes. 61
31373627 2019
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Variations for Hypothyroidism, Congenital, Nongoitrous, 4

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ClinVar genetic disease variations for Hypothyroidism, Congenital, Nongoitrous, 4:

6 ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 TSHB NM_001277991.1(TSHB):c.-490G>TSNV Pathogenic 12685 rs121918669 1:115576077-115576077 1:115033456-115033456
2 TSHB NM_001277991.1(TSHB):c.-439G>ASNV Pathogenic 12684 rs121918668 1:115576128-115576128 1:115033507-115033507
3 TSHB TSHB, 1-BP DEL, 313Tdeletion Pathogenic 12686
4 TSHB NM_000549.4:c.162+5G>ASNV Pathogenic 12688 1:115576150-115576150 1:115033529-115033529
5 TSHB NM_000549.4(TSHB):c.373delT (p.Cys125Valfs)deletion Pathogenic/Likely pathogenic 437070 rs755485552 1:115576804-115576804 1:115034183-115034183
6 TSHB NM_001277991.1(TSHB):c.70C>T (p.Gln24Ter)SNV Likely pathogenic 12687 rs121918670 1:115576636-115576636 1:115034015-115034015
7 TSHB NM_000549.4(TSHB):c.40A>G (p.Thr14Ala)SNV Benign 256640 rs10776792 1:115576023-115576023 1:115033402-115033402
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Expression for Hypothyroidism, Congenital, Nongoitrous, 4

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Search GEO for disease gene expression data for Hypothyroidism, Congenital, Nongoitrous, 4.
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Pathways for Hypothyroidism, Congenital, Nongoitrous, 4

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Pathways related to Hypothyroidism, Congenital, Nongoitrous, 4 according to KEGG:

36
# Name Kegg Source Accession
1 Thyroid hormone synthesis hsa04918

Pathways related to Hypothyroidism, Congenital, Nongoitrous, 4 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Relaxin signaling pathway 36
Show member pathways
 12.09 POU1F1 POMC GH1
2
Peptide hormone metabolism 65
Show member pathways
 11.39 TSHB POMC GH1
3
Growth hormone receptor signaling 65
Show member pathways
 10.87 PRL GH1
4
Glucocorticoid receptor regulatory network 1
10.71 PRL POU1F1 POMC
5
Antipsychotics Pathway (Metabolic Side Effects), Pharmacodynamics 60
10.46 PRL POMC
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GO Terms for Hypothyroidism, Congenital, Nongoitrous, 4

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Cellular components related to Hypothyroidism, Congenital, Nongoitrous, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 endosome lumen GO:0031904 8.62 PRL GH1

Biological processes related to Hypothyroidism, Congenital, Nongoitrous, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 response to nutrient levels GO:0031667 9.4 PRL GH1
2 positive regulation of multicellular organism growth GO:0040018 9.37 POU1F1 GH1
3 positive regulation of JAK-STAT cascade GO:0046427 9.32 PRL GH1
4 pituitary gland development GO:0021983 9.26 PROP1 POU1F1
5 JAK-STAT cascade involved in growth hormone signaling pathway GO:0060397 9.16 PRL GH1
6 adenohypophysis development GO:0021984 8.96 PROP1 POU1F1
7 somatotropin secreting cell differentiation GO:0060126 8.62 PROP1 POU1F1

Molecular functions related to Hypothyroidism, Congenital, Nongoitrous, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 prolactin receptor binding GO:0005148 8.96 PRL GH1
2 hormone activity GO:0005179 8.92 TSHB PRL POMC GH1
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Sources for Hypothyroidism, Congenital, Nongoitrous, 4

About this section
3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
The MalaCards human disease database index: 1-9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
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